Angiogenesis is the development of new blood vessels from existing microvessels. The process of generating new blood vessels plays an important role in embryonic development, in the inflammatory response, in the development of metastases (tumor induced angiogenesis or TIA), in diabetic retinopathy, in the formation of the arthritic panus and in psoriasis. Under normal physiological conditions, humans or animals only undergo angiogenesis in very specific, restricted situations. For example, angiogenesis is normally observed in wound healing, in fetal and embryonal development and in the formation of the corpus luteum, endometrium and placenta. The control of angiogenesis is a highly regulated system involving angiogenic stimulators and inhibitors. The control of angiogenesis has been found to be altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to the uncontrolled angiogenesis.
In tumor angiogenesis, for example, capillary sprouts are formed, their formation being induced by a group of tumor cells. However, compared with blood vessels produced in normal angiogenic microenvironments, tumor microvessels are morphologically and functionally unique. Their vascular networks typically show disorganized or aberrant architecture, luminal sizes vary and blood flow can fluctuate chaotically. There are two principal types of tumor angiogenesis in terms of the events which follow implantation of metastatic seedlings on surfaces and in organs. The first or primary angiogenesis is the initial vascularization of the mass of multiplying tumor cells and is regarded as an essential prerequisite for the survival and further growth of a metastatic deposit. The second is a continuing or secondary angiogenesis and is the phenomenon which occurs in waves at the periphery of a growing tumor mass. This second angiogenesis is essential for the accretion of new microcirculatory territories into the service of the expanding and infiltrating tumor.
Persistent, unregulated angiogenesis occurs in a multiplicity of disease states, tumor metastasis and abnormal growth by endothelial cells and supports the pathological damage seen in these conditions. The diverse pathological states created due to unregulated angiogenesis have been grouped together as angiogenic dependent or angiogenic associated diseases. Therapies directed to the control of the angiogenic processes could lead to the abrogation or mitigation of these diseases.
One example of a disease mediated by angiogenesis is ocular neovascular disease. This disease is characterized by invasion of new blood vessels into the structures of the eye such as the retina or cornea. It is the most common cause of blindness and is involved in approximately twenty eye diseases. In age related macular degeneration, the associated visual problems are caused by an ingrowth of choroidal capillaries through defects in Bruch's membrane with proliferation of fibrovascular tissue beneath the retinal pigment epithelium. Angiogenic damage is also associated with diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasia. Diseases associated with retinal/choroidal neovascularization include, but are not limited to, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum and Pagets disease.
Another disease in which angiogenesis is believed to be involved is rheumatoid arthritis. The blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to forming new vascular networks, the endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction.
An important area of current research in therapeutic oncology is focused on the discovery and development of anti-angiogenic agents which target tumor vasculature by inhibiting or suppressing new blood vessel growth. Several kinds of compounds have been used to prevent angiogenesis. For instance, Taylor, et al. have used protamine to inhibit angiogenesis (see, Taylor, et al., Nature 297:307 (1982)). However, the toxicity of protamine limits its practical use as a therapeutic. In addition, Folkman, et al. have disclosed the use of heparin and steroids to control angiogenesis (see, Folkman, et al., Science 221:719 (1983) and U.S. Pat. Nos. 5,001,116 and 4,994,443). Steroids, such as tetrahydrocortisol, which lack gluco- and mineral-corticoid activity, have been found to be angiogenic inhibitors. In addition, angiostatin proteins have been shown to reversibly inhibit proliferation of endothelial cells. Angiostatin is capable of inhibiting angiogenesis-related diseases and modulating angiogenic processes (see, e.g., WO 95/292420).
In view of the foregoing, it is apparent that there remains a need in the art for methods and compounds for inhibiting angiogenesis, either by competitively inhibiting an angiogenesis factor or by some other mechanism. Such methods and compounds would have an adverse effect on the growth of tumors and, in addition, could be used to treat many of the other diseases set forth above. The methods of the present invention fulfill this and other needs.